(Revised Abstract) DESCRIPTION (provided by applicant): Successful anti-tumor immunotherapy ultimately depends on the ability of immune effector cells to gain access to malignant tissues. In this project, adhesive interactions between tumor-specific cytotoxic T lymphocytes (CTL) and tumor microvessels are considered to be a locus of action for promoting tumor immunity. This research proposal addresses the hypothesis that the proinflammatory cytokine, interleukin-6 (IL-6), plays a central role in stimulating a4b7 integrin-dependent delivery of CTL to tumor tissues in response to fever-range thermal stress. This hypothesis is formulated on the basis of new information from our laboratory demonstrating that fever-range hyperthermia stimulates the binding function of the a4b7 integrin homing receptor in tumorspecific CD8+ human CTL by altering 11-6 bioactivity. Initial data indicate that fever-range whole body hyperthermia (WBH) also acts on blood vessels in murine tumor tissues to stimulate the expression of functional endothelial ligands for a4b7 integrin (i.e., MAdCAM- 1, VCAM-1). Experiments are designed to address the following specific aims: (1) To define the requirement for IL-6 in recruitment of tumorreactive CTL to tumor tissues in response to fever-range whole body hyperthermia (WBH). The role of multiple lymphocyte-endothelial molecular pairs (a4b7 integrin/MAdCAM- 1, VCAM- 1; LFA-1/ICAM- 1; PSGL-1/E-selectin, P-selectin; CCR7/SLC; CXCR3/MIG, IP-10) will be investigated. These studies focus on a novel model system in which a4b7 integrin-dependent trafficking of human CTL to autologous lung tumor xenografts will be evaluated in SCID mice. (2) To identify novel IL-6 macromolecular soluble complexes induced by thermal stress that promotes a4b7 integrin-dependent leukocyte-endothelial cell adhesion. (3) To elucidate contributions of a4b7 integrin and endogenous IL- 6 in promoting tumor-specific cytotoxic immunity in response to combination fever range WBH and hsp110/grp170 vaccination. This project is highly interactive with Project 1 (John Subjeck) and Project 2 (Elizabeth Repasky) in which novel tumor vaccination strategies are developed using hsp 110 and grp 170 to initiate tumor-specific CTL responses in mouse models. Moreover, the success of this proposal is dependent on support from the core resources for administrative support and scientific leadership, hyperthermia treatment of mice, analysis of cytokine levels and CTL responses, and biostatistical analysis. Results of this integrated program are expected to support our long-term goal to develop new immunotherapies for the intervention in cancer.